The new compounds of formula I have not been described previously either with respect to their synthesis or with respect to their pharmaceutical properties. The compounds of the present invention have substantial and decisive structural differences when compared to already known compounds with antiarrhythmic activity.
Various materials are known, for use in the therapy of heart disorders. These include, for example, quinidine, lidocaine, procainamide, mexiletin, disopyramide, mexiletin, disopyramide, propranolol and verapamil. Many of the known antiarrhythmic drugs exhibit unwanted adverse reactions and, in some case, insufficient efficacy for certain forms of arrhythmia. None of the known agents is entirely satisfactory, particularly for the for the long-term control of disordered heart activity. No generally valid rules can be defined which describe the structure-effect relationships, because the chemical structures of these various materials are very different. In particular, the therapeutic agents described show no obvious structural relationships to the compounds of the present invention.
The synthesis of lidocaine analogs is described in German Federal Republic accepted applications patent No. 2,235,745 and German Federal Republic published patent application No. 2,400,450. In particular, 2-amino-2',6'-propionoxylidide (tocainide) is named, which, in contrast to lidocaine, can also be administered orally. The structureS of these primary acylanalides are different from that of the compounds of the present invention.
Various 10-beta-dialkylaminopropionyl-2-carbalkoxyamino-phenothiazines are described in Soviet patent No. 332,835, which were shown to have antiarrhythmic, spasmolytic and other pharmacological effects. Preparations from this series, such as moracizine and ethacizine have become used in human medicine. A characteristic of this group of compounds is the phenothiazine ring, which tends to oxidize. The corresponding 5-sulfoxides are formed from these compounds due to the oxidation of the ring sulfur atom during storage and in the course of biological degradation. This weakening is progressive, until it is lost altogether. Therefore, the administration of drug forms of these materials has to be replaced at relatively short time intervals, to ensure the necessary blood levels.
The .beta.-dialkylaminopropionyl group in the 10 position is a characterizing feature of the known therapeutic drugs. This further restricts their chemical stability, because, as is well known to those skilled in the art, this substitution is associated with a beta elimination of the dialkylamino group.
Beta elimination is a disadvantage also in the case of the 3-carbalkoxyamino-5-(beta-dialkylaminopropionyl)-10,11-dihydro-5H-dibenz[b ,f]azepines, which are described in the German Democratic Republic patent No. 152,782, and in Soviet patent No. 1,089,089. Compared to the 3-carbalkoxyamino-5-dialkylaminoacetyl-10,11-dihydro-5H-dibenz[b,f]azepine s, of the last mentioned patents, the compounds of the present invention have a variety of advantageous pharmacological effects. The strength and duration of action, the therapeutic breadth and the absorption behavior advantageously differentiate the compounds of the present invention from the known materials of the aforementioned prior art.